Tumor Induced Stromal Stat1 Deregulates Mammary Tissue Homeostasis And Accelerates Breast Cancer

Abstract The tumor microenvironment (TME) – the dynamic tissue space in which the tumor exists – plays a significant role in tumor initiation and is a key contributor in cancer progression. Little is known about the tumor-induced changes in the adjacent tissue stroma. Herein, we sought to explore tumor-induced changes in the TME at the morphological and molecular level to further characterize cancer progression. We show that tumor-adjacent mammary glands (TAGs) display altered branch morphology, increased expression of αSMA particularly in myofibroblasts, and an increased capacity to form mammospheres in 2D suspension culture. FACS analysis showed that TAGs contain an increased number of Lin-CD24+/CD49+ enriched mammary gland stem cell (MaSCs) population, suggesting deregulated tissue homeostasis in TAGs. We conducted comparative transcriptomics on TAGs and contralateral control glands. Meta-analysis on differentially expressed genes from our RNA-seq dataset plus two breast cancer stromal patient microarray datasets identified shared upregulation of STAT1, which we verified in tumor-adjacent tissues. Knockdown of STAT1 in caveolin-deficient mouse embryonic fibroblasts (CAFs) cocultured with human breast cancer cells altered cancer cell proliferation, further suggesting the role of STAT1 as a stromal contributor of tumorigenesis. Furthermore, in our proof-of-concept in vivo experiment, co-treatment with fludarabine, a FDA-approved STAT1 activation inhibitor and DNA synthesis inhibitor, in combination with doxorubicin, showed enhanced therapeutic efficacy in treating mouse mammary gland tumors. Our results demonstrate that stromal STAT1 expression could promote tumor progression and is a potential therapeutic target for breast cancer. Citation Format: Victoria R. Zellmer, Patricia M. Schnepp, Sarah L. Fracci, Xuejuan Tan, Erin N. Howe, Siyuan Zhang. Tumor induced stromal STAT1 deregulates mammary tissue homeostasis and accelerates breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2983. doi:10.1158/1538-7445.AM2017-2983